Behavioural Correlates of Dopaminergic Agonists’ Dyskinetic Potential in the 6-OHDA-Lesioned Rat

  • Anna R. Carta
  • Lucia Frau
  • Annalisa Pinna
  • Micaela Morelli
Conference paper
Part of the Advances in Behavioral Biology book series (ABBI, volume 58)


Prolonged treatment with l-DOPA induces highly disabling dyskinesia in patients affected by Parkinson’s disease (PD). In contrast, dopamine receptor agonist treatments display dyskinetic outcome variably, depending on pharmacokinetic/pharmacodynamic drug profile. The present study was aimed at assessing behavioural correlates of intense or mild dyskinesia displayed by the different dopamine receptor stimulation in the 6-hydroxydopamine rat model of PD. Sensitization of contralateral turning behaviour (SCT) and abnormal involuntary movements (AIMs) were assessed as behavioural correlates of dyskinetic responses during subchronic stimulation of the D1 receptor by SKF38393 and the D2/D3 receptors by ropinirole. Similarly to what already has been described for l-DOPA, subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Evaluation of both behavioural responses represents a useful test to predict the dyskinetic potential of drugs in preclinical screening.


Behavioural Correlate Dopaminergic Agonist Subchronic Treatment Contralateral Turning Agonist Ropinirole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank GlaxoSmithKline (Harlow, Essex, UK) for providing ropinirole. This work was supported by a grant from MURST – project FIRB (RBNE03YA3L-2005).


  1. Adler CH, Sethi KD, Hauser RA, Davis TL, Hammerstad JP, Bertoni J, Taylor RL, Sanchez-Ramos J and O’Brien CF (The Ropinirole Study Group Neurology) (1997) Ropinirole for the treatment of early Parkinson’s disease. Eur J Neurol 49: 393–399.Google Scholar
  2. Andringa G, Lubbers L, Drukarch B, Stoof JC and Cools AR (1999a) The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson’s disease: effects of l-DOPA and the D1 agonist SKF 82958. Behav Pharmacol 10: 175–182.CrossRefPubMedGoogle Scholar
  3. Andringa G, Vermeulen RJ, Drukarch B, Renier WO, Stoof JC and Cools AR (1999b) The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson’s disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297. Behav Pharmacol 10: 163–173.CrossRefPubMedGoogle Scholar
  4. Blanchet PJ, Gomez-Mancilla B and Bedard PJ (1995) DOPA-induced “peak dose” dyskinesia: clues implicating D2 receptor-mediated mechanisms using dopaminergic agonists in MPTP monkeys. J Neural Transm 45: S103-S112.Google Scholar
  5. Blanchet PJ, Grondin R and Bédard PJ (1996) Dyskinesia and wearing-off following dopamine D1 agonist treatment in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates. Mov Disord 11: 91–94.CrossRefPubMedGoogle Scholar
  6. Calon F, Goulet M, Blanchet PJ, Martel JC, Piercey MF, Bédard PJ and Di Paolo T (1995) Levodopa or D2 agonist induced dyskinesia in MPTP monkeys: correlation with changes in dopamine and GABAA receptors in the striatopallidal complex. Brain Res 680: 43–52.CrossRefPubMedGoogle Scholar
  7. Calon F, Morissette M, Goulet M, Grondin R, Blanchet PJ, Bedard PJ and Di Paolo T (1999) Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content. Neurochem Int 35: 81–91.CrossRefPubMedGoogle Scholar
  8. Carta AR, Pinna A and Morelli M (2006) How reliable is the behavioural evaluation of dyskinesia in animal models of Parkinson’s disease? Behav Pharmacol 17: 393–402.CrossRefPubMedGoogle Scholar
  9. Chang JW, Wachtel SR, Young D and Kang UJ (1999) Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson’s disease: studies on medial forebrain bundle and striatal lesions. Neuroscience 88: 617–628.CrossRefPubMedGoogle Scholar
  10. Delfino MA, Stefano AV, Ferrario JE, Taravini IR, Murer MG and Gershanik OS (2004) Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias. Behav Brain Res 152: 297–306.CrossRefPubMedGoogle Scholar
  11. Fukuzaki K, Kamenosono T and Nagata R (2000) Effects of ropinirole on various parkinsonian models in mice, rats, and cynomologus monkeys. Pharmacol Biochem Behav 65: 503–508.CrossRefPubMedGoogle Scholar
  12. Giardina WJ and Williams M (2001) Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data. CNS Drug Rev Fall 7: 305–316.CrossRefGoogle Scholar
  13. Goulet M, Grondin R, Blanchet PJ, Bédard PJ and Di Paolo T (1996) Dyskinesias and tolerance induced by chronic treatment with a D1 agonist administered in pulsatile or continuous mode do not correlate with changes of putaminal D1 receptors in drug-naive MPTP monkeys. Brain Res 719: 129–137.CrossRefPubMedGoogle Scholar
  14. Guigoni C, Aubert I, Li Q, Gurevich VV, Benovic JL, Ferry S, Mach U, Stark H, Leriche L, Håkansson K, Bioulac BH, Gross CE, Sokoloff P, Fisone G, Gurevich EV, Bloch B and Bezard E (2005) Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat Disord 11: S25–S29.CrossRefPubMedGoogle Scholar
  15. Guttman M and Jaskolka J (2001) The use of pramipexole in Parkinson’s disease: are its actions D(3) mediated? Parkinsonism Relat Disord 7: 231–234.CrossRefPubMedGoogle Scholar
  16. Henry B, Crossman AR and Brotchie JM (1998) Characterization of enhanced behavioural responses to l-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson disease. Exp Neurol 151: 334–342.CrossRefPubMedGoogle Scholar
  17. Hurley MJ and Jenner P (2006) What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 111: 715–728.CrossRefPubMedGoogle Scholar
  18. Jenner P (2003) Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr Opin Neurol 16: S3–S7.CrossRefPubMedGoogle Scholar
  19. Lane EL, Cheetham SC and Jenner P (2006) Does contraversive circling in the 6-OHDA-lesioned rat indicate an ability to induce motor complications as well as therapeutic effects in Parkinson’s disease? Exp Neurol 97: 284–290.CrossRefGoogle Scholar
  20. Lindgren HS, Rylander D, Ohlin KE, Lundblad M and Cenci MA (2007) The “motor complication syndrome” in rats with 6-OHDA lesions treated chronically with l-DOPA: relation to dose and route of administration. Behav Brain Res 177: 150–159.CrossRefPubMedGoogle Scholar
  21. Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N and Cenci MA (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15: 120–132.CrossRefPubMedGoogle Scholar
  22. Marin C, Rodriguez-Oroz MC and Obeso JA (2006) Motor complications in Parkinson’s disease and the clinical significance of rotational behavior in the rat: have we wasted our time? Exp Neurol 197: 269–274.CrossRefPubMedGoogle Scholar
  23. Matsuda H, Hiyama Y, Terasawa K, Watanabe H and Matsumoto K (1992) Enhancement of rotational behavior induced by repeated administration of SKF38393 in rats with unilateral nigrostriatal 6-OHDA lesions. Pharmacol Biochem Behav 42: 213–218.CrossRefPubMedGoogle Scholar
  24. Morelli M, Fenu S, Garau L and Di Chiara G (1989) Time and dose dependence of the ‘priming’ of the expression of dopamine receptor supersensitivity. Eur J Pharmacol 162: 329–335.CrossRefPubMedGoogle Scholar
  25. Olsson M, Nikkhah G, Bentlage C and Bjorklund A (1995) Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15: 3863–3875.PubMedGoogle Scholar
  26. Pearce RK, Banerji T, Jenner P and Marsden CD (1998) De novo administration of ropinirole and bromocriptine induces less dyskinesia than l-dopa in the MPTP-treated marmoset. Mov Disord 13: 234–241.CrossRefPubMedGoogle Scholar
  27. Pellegrino A, Pellegrino AS and Cushman AJ (1979) Stereotaxic Atlas of the Rat Brain. Plenum Press, New York.Google Scholar
  28. Pinna A, Fenu S and Morelli M (2001) Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse 39: 233–238.CrossRefGoogle Scholar
  29. Pinna A, Pontis S and Morelli M (2006) Expression of dyskinetic movements and turning behaviour in subchronic l-DOPA 6-hydroxydopamine-treated rats is influenced by the testing environment. Behav Brain Res 171: 175–178.CrossRefPubMedGoogle Scholar
  30. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE and Lang AE (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 342: 1484–1491.CrossRefPubMedGoogle Scholar
  31. Rascol O, Nutt JG, Blin O, Goetz CG, Trugman JM, Soubrouillard C, Carter JH, Currie LJ, Fabre N, Thalamas C, Giardina WW and Wright S (2001) Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch Neurol 58: 249–254.CrossRefPubMedGoogle Scholar
  32. Ravenscroft P, Chalon S, Brotchie JM and Crossman AR (2004) Ropinirole versus l-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson’s disease: implications for dyskinesia. Exp Neurol 185: 36–46.CrossRefPubMedGoogle Scholar
  33. Reichmann H (2000) Long-term treatment with dopamine agonists in idiopathic Parkinson’s disease. J Neurol 247: S17–S19.CrossRefGoogle Scholar
  34. Sethi KD, O’Brien CF, Hammerstad JP, Adler CH, Davis TL, Taylor RL, Sanchez-Ramos J, Bertoni JM and Hauser RA (1998) Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Arch Neurol 55: 1211–1216.CrossRefPubMedGoogle Scholar
  35. Setler PE, Sarau HM, Zirkle CL and Saunders HL (1978) The central effects of a novel dopamine agonist. Eur J Pharmacol 50: 419–430.CrossRefPubMedGoogle Scholar
  36. Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39: 777–787.CrossRefPubMedGoogle Scholar
  37. Silverdale MA, Nicholson SL, Ravenscroft P, Crossman AR, Millan MJ and Brotchie JM (2004) Selective blockade of D(3) dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate. Exp Neurol 188: 128–138.CrossRefPubMedGoogle Scholar
  38. Smith LA, Jackson MJ, Al-Barghouthy G and Jenner P (2002) The actions of a D-1 agonist in MPTP treated primates show dependence on both D-1 and D-2 receptor function and tolerance on repeated administration. J Neural Transm 109: 123–140.CrossRefPubMedGoogle Scholar
  39. Smith LA, Jackson MJ, Johnston L, Kuoppamaki M, Rose S, Al-Barghouthy G, Del Signore S and Jenner P (2006) Switching from levodopa to the long-acting dopamine D2/D3 agonist piribedil reduces the expression of dyskinesia while maintaining effective motor activity in MPTP-treated primates. Clin Neuropharmacol 29: 112–125.CrossRefPubMedGoogle Scholar
  40. Van de Witte SV, Drukarch B, Stoof JC and Voorn P (1998) Priming with l-DOPA differently affects dynorphin and substance P mRNA levels in the striatum of 6-hydroxydopamine-lesioned rats after challenge with dopamine D1-receptor agonist. Brain Res Mol Brain Res 61: 219–223.CrossRefPubMedGoogle Scholar
  41. Xiao D, Bastia E, Xu YH, Benn CL, Cha JH, Peterson TS, Chen JF and Schwarzschild MA (2006) Forebrain adenosine A2A receptors contribute to l-3,4-dihydroxyphenylalanine-induced dyskinesia in hemiparkinsonian mice. J Neurosci 26: 13548–13555.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Anna R. Carta
    • 1
  • Lucia Frau
    • 1
  • Annalisa Pinna
    • 1
  • Micaela Morelli
    • 1
  1. 1.Department of ToxicologyUniversity of CagliariCagliariItaly

Personalised recommendations